Hormone replacement therapy (HRT) has been used worldwide to relieve menopausal symptoms. The evolution in clinical knowledge of its risks has lagged persistently behind its application in clinical practice. In the 1970s, endometrial cancer incidence increased in developed countries, and exogenous estrogen therapy in postmenopausal women was the most important factor. In the 1980s and 90s, combined estrogen-progesterone therapy was prescribed on a large scale, based on its potential beneficial effects on the musculoskeletal and cardiovascular systems without increasing the risk of endometrial carcinoma. However, once again, recent reports argue against the safety of HRT, and the most important issues are now the increased risk of cardiovascular disease and total cancer in combined formulations. We conclude that the recently reported risks on combined HRT may have a significant public health impact, and that this treatment regimen should not be prescribed to protect postmenopausal women from endometrial carcinoma, since the risks outweigh the benefits.